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12 Articles in Volume 16, Issue #10
2016 Practical Clinical Advances: Ketamine and Metformin
Case Challenge: Amniotic Allograft Reduces Joint and Soft Tissue Pain
Challenges of Treating Young Patients With a Terminal Prognosis
Defining Palliative Care
Discussing Benefits of Palliative Care
Evaluation of Antiemetic Pharmacotherapy in the Setting of Opioid Withdrawal
Fibromyalgia, Chronic Fatigue, and Chronic Fatigue Syndrome
Gabapentin Dosing for Neuropathic Pain
IV Acetaminophen Reduces Need for Opioids in Burn Patients
Opioid-Induced Constipation: New and Emerging Therapies—Update 2016
Osteopathic Treatment Considerations For Head, Neck, and Facial Pain
Tips From the Field: Deconstructing the Art of Headache Medicine

Fibromyalgia, Chronic Fatigue, and Chronic Fatigue Syndrome

Clinicians can benefit from a clearer distinction between 3 overlapping syndromes that are each impacted by sleep and symptoms of depression.

Editor’s Note: This article is excerpted from Dr. Goldenberg’s new book, Chronic Widespread Pain: Lessons Learned from Fibromyalgia and Related Disorders. To purchase the entire e-book, go to ppmjournal.com/fibro and use the promo code READPPM for a 15% discount.

Persistent exhaustion is almost always present in patients with fibromyalgia (FM) and is prominent in each of the overlapping chronic functional illnesses, including irritable bowel syndrome (IBS), chronic migraine, and chronic bladder and pelvic pain. Unfortunately, there is no universal definition of what constitutes pathologic fatigue. The most common description of excess fatigue suggests that it is an extreme and persistent form of mental and/or physical tiredness, weakness, or exhaustion.

Chronic fatigue, like chronic pain, is a common symptom in the general population, with prevalence estimates between 10% and 40%.

Unexplained chronic fatigue, like FM, was described in the 1800s. In 1869, Dr. George Beard reported severe exhaustion accompanied by a constellation of symptoms, including “headaches, dyspepsia, insomnia, anesthesia, neuralgia, and rheumatic gout,” the term used at that time for joint and muscle pain.1 Beard termed this neurasthenia (chronic exhaustion) and suggested it resulted from changes in the central nervous system: “My own view is that the central nervous system . . . probably undergoes slight, undetectable, morbid changes in its chemical structure and as a consequence becomes more or less impoverished in the quantity and quality of its nervous force.”1

Chronic fatigue, like chronic pain, is a common symptom in the general population, with prevalence estimates between 10% and 40%. In 1 study, nearly 20% of 31,000 men and women (age 18 to 45) in a general practice reported substantial fatigue lasting 6 months or longer.2 During the past decade, most studies have defined chronic fatigue as fatigue lasting 6 months or longer with fatigue scores of 8 or greater on the Fatigue Scale.3 Women are more likely to report fatigue and more often report severe fatigue.2-4 The prevalence of fatigue was 30% in older women compared with 15% in older men.5

Chronic pain and chronic fatigue are strongly associated. In a general population-based survey, chronic fatigue (occurring in 5% to 12%) overlapped with chronic widespread pain, chronic orofacial pain, and IBS.6 The occurrence of multiple syndromes was greater than would be expected by chance. Factors that were common across syndromes included female gender and high levels of anxiety related to health, such as medical worry preoccupation.

In a second study, the authors reported persistent fatigue in 60% of the 451 subjects with chronic widespread pain, and chronic widespread pain was reported in 33% of 809 responders who had persistent fatigue.7 In addition, anxiety and depression were more common in subjects who reported both symptoms than in those who reported either 1 or neither. “Participants who had chronic disease, high body mass index, low activity levels, or did not perceive ability to influence health, had higher adjusted odds of reporting both symptoms [but not 1 alone] than subjects not having these characteristics,” noted the authors.7

What Causes Chronic Fatigue?

The most common causes of fatigue are chronic medical or psychiatric illnesses, accounting for 70% of chronic fatigue in the general population. However, at least 30% of the time no specific cause is found for chronic fatigue.8

In population-based studies, it has been very difficult to separate idiopathic chronic fatigue that has been associated with chronic depression and other chronic mood disturbances. Depression-associated fatigue versus “pure” fatigue was evaluated in a report that prospectively followed 1,177 primary care patients, with 3 separate measurements of fatigue and psychiatric symptoms.9 The depression and fatigue scores correlated closely over time. They replicated previous findings of a strong correlation between fatigue and psychiatric morbidity, but also identified a group of patients with persistent, independent fatigue, which was not associated with any increase in psychological morbidity. This persistent, independent fatigue state (lasting for 6 months) was uncommon and found in only 2.5% of the population.

In data from the second British National Survey of Psychiatric Morbidity, “the prevalence of chronic fatigue was 15% and this was significantly associated with the number of reported physical illnesses. Chronic fatigue was strongly associated with the presence of depressive symptoms [OR 5.37], anxiety-related symptoms [OR 4.66], and sleep complaints [OR 4.41]. After adjustment for all sociodemographic and psychiatric factors, the number of reported physical illnesses was less strong but still significantly associated with chronic fatigue.”10

In a population survey of more than 10,000 adolescents, 13 to 18 years old, chronic fatigue was found in 3%, of which one-half had associated depression or anxiety.11 Although the prevalence is lower than in adults, more than half the adolescents with chronic fatigue had severe or very severe disability. Comorbid mood correlated with greater disability and health service utilization.

In a study of adults over 60, the overall prevalence of fatigue was 27%, much higher than that seen in adolescents.12 As with younger adults, most cases were associated with a psychological disorder, and psychological disorders were more predictive of chronic fatigue than physical illness. However, distinct forms of physical and psychological fatigue could be identified.

Assessment of Chronic Fatigue

In an observational cohort study involving 147 primary care practices, the authors described 4 distinct patterns of chronic fatigue: “26% of patients had continuously high scores for fatigue, 17% had a fast recovery, 25% had a slow recovery, and 32% initially improved but then had a recurrence of fatigue.”13 The authors also found a longitudinal relationship with fatigue severity and impaired functioning, psychological symptoms, and poor sleep. These same investigators reported that changes in pain and fatigue were directly related in time.14

There are 3 different instruments commonly used to measure fatigue: the Patient-Reported Outcome Measurement Information System (PROMIS) instrument, the Functional Assessment of Chronic Illness Therapy-Fatigue (FACIT-F), and the SF-36v2 Vitality subscale.15 Fatigue was associated with gender, being significantly more common in younger females. Greater education and being married correlated with less fatigue.

In order to better characterize fatigue states in various subspecialties, a cross-sectional sample of women with chronic fatigue syndrome (CFS), post-cancer fatigue, or fatigue associated with depression were evaluated with a specific instrument.16 The instrument was able to differentiate CFS from major depression.

Defining Chronic Fatigue Syndrome

There has been considerable controversy over whether CFS is a specific disorder or at the severe end of the spectrum of idiopathic exhaustion. There also has been confusion regarding the overlap of CFS with FM and other functional somatic syndromes, and with psychiatric illness. In some reports the majority of subjects with CSF also have a comorbid psychiatric disorder, and psychiatric disorders increase the risk of later chronic fatigue. Some researchers have claimed that fatigue cannot be distinguished from depression, whereas others believe chronic fatigue should be considered a separate diagnostic category.

CFS was first identified as a new illness in 1985 following a series of 31 cases of unexplained fatigue reported from Lake Tahoe, Nevada.17 In the report, the authors presented initial evidence that the Lake Tahoe cases were related to the Epstein-Barr virus. Chronic exhaustion, or neurasthenia, had previously been linked to potential infections, including outbreaks reported from Los Angeles County General Hospital in 1934.18 During the next 50 years, other epidemics of exhaustion, generalized body aches, and general misery were reported from South Africa, Australia, England, as well as in Florida and Washington, DC. The clustering of cases, flu-like symptoms, and the beliefs of healthcare professionals suggested an infectious etiology but none was ever found.

Subsequently, a large number of reports from various laboratories failed to find a significant association between CFS and the Epstein-Barr virus.19 Other potential viral associations with CFS have been proposed but none have held up to careful scrutiny. In the largest prospective trial, there was no difference in murine retroviral sequences between CFS and control subjects.20

A number of CFS case definitions, based on symptoms, have been proposed and then field-tested.21 The initial Centers for Disease Control and Prevention case definition,22 which reflected the consensus in 1994, included the following criteria: Severe chronic fatigue for 6 or more consecutive months that is not due to ongoing exertion or other medical conditions associated with fatigue (these other conditions need to be ruled out by a doctor after diagnostic tests have been conducted); the fatigue significantly interferes with daily activities and work; and the individual concurrently has 4 or more of the following 8 symptoms:

  • post-exertion malaise lasting more than 24 hours
  • unrefreshing sleep
  • significant impairment of short-term memory or concentration
  • muscle pain
  • pain in the joints without swelling or redness
  • headaches of a new type, pattern, or severity
  • tender lymph nodes in the neck or armpit
  • a sore throat that is frequent or recurring

Applying the CDC criteria, the prevalence of CFS ranges from 0.24% to 0.42% in the United States but up to 0.68% in other regions.23  The prevalence of CFS was higher among women, 373 per 100,000 persons. Utilizing different case definitions, the minimal prevalence of CFS was 0.2%.24

In 2015, the Institute of Medicine (IOM) used a consensus panel to provide what was described as “evidence-based clinical diagnostic criteria for ME/CFS for use by clinicians,” and recommended a new diagnostic term, Systemic Exertion Intolerance Disease (SEID).25 According to the IOM diagnostic criteria, a patient must have the following 3 symptoms:

  • A substantial reduction or impairment in the ability to engage in pre-illness levels of occupational, educational, social, or personal activities that persists for more than 6 months and is accompanied by fatigue, which is often profound, is of new or definite onset (not lifelong), is not the result of ongoing excessive exertion, and is not substantially alleviated by rest
  • Postexertional malaise
  • Unrefreshing sleep.

At least 1 of the 2 following manifestations is also required:

  • cognitive impairment
  • orthostatic intolerance

Furthermore, patients should have these symptoms at least half of the time with moderate, substantial, or severe intensity.

Based on this new definition, it was estimated that 1 million to 2.5 million Americans have CFS/SEID, with direct and indirect economic costs between $17 billion and $24 billion annually.25,26. The report commented that previous terms myalgic encephalomyelitis and CFS were “unacceptable to many patients and their advocates, who reported that this term leads clinicians and others to belittle or even dismiss their disease.” This report emphasized that the illness “is not, as many clinicians believe, a psychological problem,” and objective abnormalities exist.27

Overlapping Symptoms: Fatigue, Mood, Pain

It is not clear that this updated definition for CFS will advance the understanding of the disorder or its acceptance as a diagnosable condition.22,25 There was little evidence that the new case definition was an improvement over prior CFS case definitions given continued diagnostic uncertainty.28 The new diagnostic criteria do not offer clinicians the ability to distinguish CFS from overlapping functional somatic syndromes, and in particular FM.

Most studies have found a significant clinical overlap of FM and CFS symptoms, with the majority of individuals meeting criteria for both syndromes.29,30 In 1 report, 50 patients with primary FM who had been followed in an academic rheumatology practice frequently reported symptoms thought to be typical of chronic Epstein-Barr virus infection (CFS), but not of FM. These included recurrent sore throat (54%), recurrent rash (47%), chronic cough (40%), recurrent adenopathy (33%), and recurrent low-grade fevers (28%).29 In 55% of the patients, the illness had begun suddenly, with what seemed to be a viral syndrome.30 However, antibody titers to Epstein-Barr virus in the patients were not significantly different from those in age- and sex-matched “healthy” and “unhealthy” control subjects.30 This overlap is not surprising since fatigue is the second most prominent symptom in FM, right after chronic widespread pain.

Fatigue has been an important measure in FM research, as highlighted in 2 prominent studies: Outcome Measures in Rheumatology (OMERACT) and the PROMIS trial.31,32 The PROMIS fatigue data included 95 items that evaluate for all aspects of fatigue and their impact.32 The levels of fatigue generally have correlated well with levels of pain in FM.

As in FM and the overlapping functional somatic syndromes, the case definition and clinical expression of CFS are significantly affected by comorbid mood and sleep disturbances. For example, 1 report found that the “prevalence rates of CFS, FM, and IBS were 1.3%, 3.0%, and 9.7%, respectively, in a general population study.”33 Individuals with CFS, FM, and IBS had significantly more mood and anxiety disorders than controls. In addition, individuals with CFS more often presented with mood and anxiety disorders than did individuals with FM or IBS.33

In a population survey of 3,000 subjects, only 1% met the criteria for CFS.34 CFS was more common among females but there was no association with social class and education. Also, there was an association with early onset of depression, and often the depression preceded the CFS diagnosis, and the severity of psychiatric symptoms correlated with patients who developed CFS.35

Pain Catastrophizing

There is a strong association of chronic fatigue and CFS with pain catastrophizing.36-38 Pain catastrophizing, defined as magnification, rumination, and feelings of hopelessness related to real or anticipated pain, was associated with the levels of chronic pain in individuals with CFS.36 There was also a significant relationship between pain and depression.37 Pain catastrophizing accounted for 41% of the variation in bodily pain in female CFS patients who also reported widespread pain.38

As has been noted in FM and IBS, as well as in depression, there is a strong association between experiences of childhood stressors and the presence of CFS.39 A case-control study of 113 persons with CFS and 124 healthy subjects found that those with CFS had significantly higher levels of childhood trauma and psychological symptoms compared to controls.40 Exposure to childhood sexual abuse, emotional abuse, or emotional neglect was associated with a 6-fold increased risk of CFS. There was a graded relationship between the levels of stress and CFS risk. The outcome and potential for recovery from chronic widespread pain has been correlated with psychosocial issues and depression.41

Distinguishing Between Fatigue and Daytime Sleepiness

CFS, like FM, has been linked to sleep disturbances.42-45 To explore the impact of sleep in CFS, the sleep patterns of 14 CFS patients were assessed using electroencephalograms (EEGs) to measure slow wave sleep (SWS) and sleep efficiency.42 Guilleminault et al found that SWS percentage and sleep efficiency were lower and there was a significant increase in delta 1 (slow delta) relative power in the chronic fatigue group when compared to controls.42 Poor sleep was evaluated by monitoring non-rapid eye movement sleep and calculating cyclic alternating pattern (CAP) rate. Patient complaints of chronic fatigue and unrefreshing sleep were associated with an abnormal (greater) CAP rate (reflected as 2 distinct EEG patterns). These specific patterns were related to subtle, undiagnosed sleep-disordered breathing (an increase in respiratory effort and decrease in nasal flow) as related to an abnormal CAP rate.

Since patients with CFS exhibit daytime sleepiness, Neu and his team examined objective and subjective sleepiness in order to distinguish these symptoms from fatigue.43 In this study, patients with CFS were compared to individuals with sleep associated hypersomnia (sleep apnea-hypopnea syndrome [SAHS]) and healthy controls. The authors noted that the “mean sleep latency (SL) was significantly shorter in SAHS patients than in CFS patients and CFS patients showed significantly shorter mean SL than matched controls—but within normal range.”43 From the findings, it appeared that patients with CFS showed the highest intensity for affective symptoms. Compared to the group with SAHS, the CFS patients had higher subjective fatigue and lower subjective and objective sleepiness. Despite having similar total sleep time, the patient groups differed primarily in sleep efficiency, wake after sleep onset, duration of light sleep and slow wave sleep, as well as in sleep fragmentation and respiratory disturbance.43  

Neu and another research team explored the relationship between fatigue and sleepiness in a second study in which the patients underwent polysonography and psychometric assessments to differentiate fatigue, mood disorders, sleepiness, and sleep quality.44 Patients with CFS appeared to have a compromised sleep disregulation, which suggests that their state of unresolved fatigue cannot be resolved with improved sleep, and offers clinicians more insight regarding the distinction between fatigue and sleepiness.

Recognizing the frequent coexistence of CFS and FM, sleep-disordered
breathing has been linked only to FM but not CFS. researchers evaluated patients with defined poor sleep due to either disordered breathing or insomnia; the goal was to access symptoms of CFS as compared to FM for sleep-related indications.45 Chronic fatigue syndrome occurred frequently in subjects with sleep-disordered breathing and insomnia, but FM occurred frequently only in insomnia.45

Pain in CFS

The exact prevalence and nature of widespread pain in CFS has not been confirmed, so Meeus and colleagues conducted a review of the literature in an effort to distinguish widespread pain as a unique symptom from that of fatigue in patients with CFS.46 In appraising 25 articles, only 11 focused on musculoskeletal pain in patients with CFS. While there was no consistent definition for pain, the authors concluded that there was insufficient consensus to determine prevalence, but it was evident that chronic pain is a disabling feature of CFS.46 Looking for clarity, Meeus followed up with a case control study looking at hyperalgesia in patients with CFS.47 By examining pressure pain thresholds (PPTs) in 30 CFS patients with chronic pain, the researchers found that patients with CFS had significantly lower PPTs compared with controls. According to the findings, the mean PPT was 3.30 kg/cm2 in all CFS patients compared with 8.09 kg/cm2 in the controls, with no confounding factors responsible for the observed differences, such as catastrophizing and depression.47

In a cross-sectional study by Winger,48 this team looked at the diffuse noxious inhibitory control given its role as an endogenous pain modulatory pathway, and they confirmed its involvement in systemic pain among patients with CFS. CFS patients and 31 healthy controls “were subjected to spatial summation of thermal noxious stimuli by gradual immersion (ascending or descending) of the arm in warm water.48 While overall pain ratings were higher in CFS patients, the progression was not different between the groups. The researchers suggested that there may be a delayed pain inhibition with CFS, but the data was preliminary. A significant association exists between endogenous pain inhibition and cognitive function in patients with both CFS and FM, whereas self-reported pain was more predictive of cognitive function in individuals with CFS only.48

Cortisol, Pain, Exertion And CFS

A number of reports suggest cortisol levels may be a marker for neuroendocrine dysfunction in CFS.49-51 One study found that salivary cortisol levels were significantly lower in CFS patients than in healthy controls.49 Depressed cortisol levels correlated with decreased sleep in these adolescent patients with CFS. Similarly, altered cortisol responsiveness was noted in patients with CFS who exhibited a heightened response to exhaustion following exertion.50

Meeus et al continued an exploration of pain in patients with CFS by focusing on cortisol levels to assess intensity of pain.51 Responses of CSF patients with chronic pain were evaluated for evidence of deficient endogenous pain inhibition as the cause of their chronic widespread pain, using an immersion test. The authors found that pain inhibition began more slowly in patients with CFS than healthy controls, and they concluded that the delayed response may help explain the chronic, widespread pain commonly experienced in patients with CFS,51 and by extension FM.

A new avenue of research is the use of resting-state functional magnetic resonance imaging (fMRI) to explore connectivity between functionally linked, but physically separated, regions of the brain. The value of this technique has been an ability to detect abnormalities in functional connectivity at the level of the pain-processing pathway.52 Resting-state functional connectivity is considered a marker of chronic pain conditions, but this marker had not been examined specifically in patients with CFS. Kim and colleagues employed fMRI to demonstrate significant differences in functional connectivity in direct proportion to the degree of severity of chronic fatigue, among female patients with combined myalgic encephalomyelitis and CFS.53

Fatigue has been associated with inhibition of basal ganglia function in neurologic disorders as well as in patients who suffer from chronic immune stimulation,54 but fatigue has not been evaluated specifically in patients with CFS. However, patients with CFS have exhibited increased immune activity as would be expected in an autoimmune condition. Using functional magnetic resonance imaging (fMRI), changes in neural activation in the basal ganglia was evaluated in patients with CFS in response to a monetary gambling reward task.54 Compared to controls, patients with CFS exhibited a significant decrease in brain activation that was significantly correlated with increased mental fatigue, general fatigue, and reduced activity as evaluated using the Multidimensional Fatigue Inventory, confirming brain changes associated with fatigue in patients with CFS.

It is important for clinicians to be able to distinguish between physical fatigue caused by exertion and the malaise that is a central feature of CFS. The ability to accurately define fatigue in patients with CFS is complicated by patients’ resistance to increased physical activity that results in heightened and protracted fatigue. To better understand the processes of physical exertion and the lasting fatigue, patients with CFS were physically challenged to assess pain and fatigue responses.55 The CFS patients showed a heightened heat hyperalgesia in response to exercise-related fatigue that correlates with sensitization of the fatigue pathways.


The shared symptoms and common co-occurrence of pain among individuals is very prominent in FM, as well as in the overlapping functional pain disorders, including CFS. It has been very difficult to separate fatigue symptoms from those of sleep and mood disturbances, both in clinical and pathophysiologic studies. As with FM, there continues to be controversy with regard to CFS as a unique disease or as a manifestation of extreme severity at the end of a spectrum of chronic exhaustion.

Update 7/5/19: See latest updates on the pathophysiology of CFS here.

Last updated on: July 25, 2019
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